tbuckley/cabot-search huggingface dataset:
Abstract 2782: Small molecule H182 suppresses Stat3 activation in tumor cells and combines with radiation therapy to block breast tumor growth in mouse syngeneic models
Authors: Yue Chen, Peibin Yue, Wenzhen Fu, Weiliang Chen, Kathleen M. Kershaw, Stephen L. Shiao, Marcus A. Tius, Francisco Lopez-Tapia, James Turkson
Journal: Cancer Research (2023)

Abstract Signal transducer and activator of transcription 3 (Stat3) is a latent transcription factor that contributes to tumor cell growth and survival in constitutively-active form in several types of human cancers, and hence, serves as a therapeutic target. The azetidine-based compound, H182 irreversibly binds to Stat3. In cell-free DNA-binding assay, H182 selectively inhibited Stat3 DNA-binding activity (IC50 0.38-0.66 μM) over Stat1 or Stat5 (IC50&amp;gt;15.8 μM) in vitro. In treated pancreatic cancer cells, H182 specifically blocked the association of Stat3 with gp130 and JAK2, and inhibited Stat3 tyrosine phosphorylation and DNA-binding activity. Coimmunoprecipitation and colocalization studies of hemagglutinin (HA)-tagged Stat3 and EGFP-tagged Stat3 expressed in prostate cancer cells showed that treatment with H182 blocked the HA-Stat3:EGFP-Stat3 interactions in intact cells. Immunofluorescence staining with laser-scanning confocal microscopy analysis for the intracellular localization of Stat3 showed treatment of H182 disrupted Stat3 nuclear accumulation and promoted the aggregation of Stat3 at the perinuclear region. H182 consequently suppressed Stat3-dependent transcriptional activity and the expression of Stat3 downstream genes, including Cyclin A, Bcl-2, Cyclin B1, and Mcl-1. Moreover, H182 significantly inhibited the colony survival, migration, and invasion in vitro of breast, pancreatic and prostate cancer cells harboring aberrant Stat3 activation. Significantly, in vivo administration of H182 in combination with radiation induced a strong antitumor response against mouse triple-negative breast cancer in syngeneic models and prolonged survival. Thus, our study provides a novel Stat3 inhibitor with significant antitumor activity against human tumors cancer harboring persistently active STAT3. Citation Format: Yue Chen, Peibin Yue, Wenzhen Fu, Weiliang Chen, Kathleen M. Kershaw, Stephen L. Shiao, Marcus A. Tius, Francisco Lopez-Tapia, James Turkson. Small molecule H182 suppresses Stat3 activation in tumor cells and combines with radiation therapy to block breast tumor growth in mouse syngeneic models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2782.
Abstract 1075: Identification of resistance mechanisms to direct KRAS inhibition in pancreatic cancer
Authors: Andrew Michael Waters, Wen-Hsuan Chang, Clint Stalnecker, Cole Edwards, Runying Yang, Craig M. Goodwin, Adrienne D. Cox, Channing J. Der
Journal: Cancer Research (2023)

Abstract KRAS mutations occur in 95% of pancreatic ductal adenocarcinomas (PDAC) and are a well-validated driver of PDAC growth. Therefore, anti-KRAS therapies are expected to make a significant impact on the treatment of this deadly cancer, where there are currently no effective targeted therapies. Supporting this premise, early clinical trial results with KRASG12C inhibitors have shown promising disease control rates (84-100%) in KRASG12C-mutant PDAC. Despite these observations, two key issues limit the impact of KRASG12C inhibitors in PDAC. First, KRASG12C(OFF) mutations comprise less than 2% of KRAS mutations in PDAC. Second, patients initially responsive to KRASG12C inhibitors invariably relapse due to treatment-induced resistance. To begin qualifying KRAS inhibitors that target KRAS mutations more frequently found in PDAC, we characterized a RAS inhibitor that targets the multiple KRAS mutations as well as wild-type RAS proteins. We evaluated the impact of this inhibitor on RAS signaling and anti-proliferative activity in KRAS-mutant pancreatic cancer human cell lines and in a panel of RASless MEFs (ras-null mouse embryo fibroblasts) stably expressing exogenous RAS mutant proteins that are commonly found in PDAC. To identify genetic mechanisms of resistance to KRAS inhibition in pancreatic cancer, we applied CRISPR-Cas9 loss-of-function screens to KRASG12C-, KRASG12D-, KRASG12R-, and KRASQ61H-mutant PDAC cells treated with KRAS inhibitors to identify genes that modulate KRAS inhibitor anti-proliferative activity. We identified expected and novel mechanisms of resistance, including those that have been observed in patients treated with KRASG12C inhibitors. Citation Format: Andrew Michael Waters, Wen-Hsuan Chang, Clint Stalnecker, Cole Edwards, Runying Yang, Craig M. Goodwin, Adrienne D. Cox, Channing J. Der. Identification of resistance mechanisms to direct KRAS inhibition in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1075.
Abstract 3993: <i>In vivo</i> efficacy of an anti-human IL11RA antibody in B-hIL11RA mice with APAP-induced liver damage
Authors: Fang He, Rufeng Zhang, Mari Kuraguchi, Lei Zhao, Zhaoxue Yu
Journal: Cancer Research (2023)

Abstract Acetaminophen (N-acetyl-p-aminophenol; APAP) overdose is a common cause of drug-induced acute liver injury, thereby making APAP administration a frequently used experimental model due to its highly reproducible and dose-dependent hepatoxicity. APAP-induced liver injury (AILI) mouse models exhibited upregulated IL11 expression, indicating that targeting IL11 or its cognate receptor, IL11RA, could have therapeutic potential. To evaluate the in vivo efficacy of anti-human IL11RA antibodies in AILI mouse models, we first generated a human IL11RA knock-in mouse model (B-hIL11RA), in which human IL11RA replaced murine Il11ra, in situ. Human IL11RA mRNA and protein levels were detected in B-hIL11RA mice. We next examined whether therapeutic inhibition of IL11 signaling was effective in reducing AILI following administration of an anti-human IL11RA antibody. In vivo efficacy data showed that anti-human IL11RA antibody inhibited all aspects of AILI, including hepatocyte death (ALT, AST and TUNEL) and centrilobular necrosis. These data suggest that B-hIL11RA mice are an effective tool for preclinical in vivo efficacy evaluation of therapeutic anti-human IL11RA antibodies. Citation Format: Fang He, Rufeng Zhang, Mari Kuraguchi, Lei Zhao, Zhaoxue Yu. In vivo efficacy of an anti-human IL11RA antibody in B-hIL11RA mice with APAP-induced liver damage. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3993.
Abstract 1365: The spatially resolved host-microbiome sequencing platform reveals the interaction between bacteria and cancer stem cell microinches
Authors: Gyeongjun Kim
Journal: Cancer Research (2023)

Abstract The tumor microbiome is a unique element that appears differently for each type of cancer in a person. Currently, intratumoral host-microbiome sequencing was only done by bulk tissue analysis which means little is understood when it comes to the spatial distribution of microbiota in the heterogeneous tumor microenvironment and the localized effect of the microbiota. Breast cancer is known to be one of the cancers rich in the microbiome. We focused on cancer stem cell-like microniches related to the tumor microenvironment of triple-negative breast cancer(TNBC). We adapted SLACS(Spatially resolved Laser activated Cell Sorter) which isolates the region of interest from immunofluorescence-stained samples using a laser, providing the spatial distribution of localized microbiota in rare cancer stem cell samples. By applying SLACS to point out the breast cancer stem cell micro-niches, we discovered that more microbes flourished in ALDH1 high/CD44 high groups rather than normal cells. We also identified the composition of the microbiota was different in cancer stem cells depending on the degree of expression of the marker. Comparing RNA-seq data of host and microbiome sequencing with functional studies, we reveal the distribution of microbiota in breast tumors and interactions between cancer stem cells and microbiota. Collectively, we found the spatial pattern of the microbiota localized in cancer stem cell microniches and how cells and bacteria interact with each other more precisely. Citation Format: Gyeongjun Kim. The spatially resolved host-microbiome sequencing platform reveals the interaction between bacteria and cancer stem cell microinches [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1365.
Abstract 5647: Single cell, multiomic spatial phenotyping of immunotherapy responses in head and neck cancer
Authors: HaYeun Ji, Niyati Jhaveri, Ning Ma, Bassem B. Cheikh, Aditya Pratapa, James Monkman, Ken O’Byrne, Brett Hughes, Arutha Kulasinghe, Oliver Braubach
Journal: Cancer Research (2023)

Abstract Background: Immune checkpoint inhibitors (ICI) have proven to be game-changing treatments for mucosal head and neck squamous cell cancer (HNSCC). Emerging successes with anti-PD-1/PD-L1 therapy have led to durable responses and prolonged survival in both human papillomavirus-positive (HPV+) and negative (HPV-) patients. There is now a need for predictive biomarkers to guide patient selection for highly targeted ICI therapies as currently available diagnostic biomarkers have a limited value. The tumor microenvironment (TME) composition, contexture, and cellular architecture are now recognized as key to understanding immune responsive and resistant phenotypes. Here, we are using a spatial biology approach to explore the TME in metastatic/recurrent HNSCC tumors treated with Pembrolizumab/Nivolumab. Methods: In this study, we used single cell, multiomic spatial phenotyping utilizing the PhenoCycler-Fusion spatial biology platform to characterize the TME of HNSCC tumors from a cohort of n=40 patients. The discovery cohort consisted of patients who had complete vs. partial vs. stable vs. progressive responses to ICI therapy. We first analyzed tissues using an ultrahigh-plex antibody panel of &amp;gt;60 antibodies that label immune cell lineages, checkpoints, activation markers as well as tissue structure and the stroma. We then conducted whole-slide, single cell resolution RNA detection with complementary markers on serial sections from the same tissue blocks; the combination of these data allowed us to obtain multiomic spatial signatures that offered uniquely comprehensive insight into the TME of our tissue cohorts. Results: Our study identified highly resolved tissue immune contexture analysis and metabolic tissue signatures associated with resistance and sensitivity to immunotherapy. Most notably, multiomic profiling of HNSCC tumours provided deeper insights into ICI therapy resistance than the single omics based approaches alone. Conclusions: Our study demonstrates the power of unbiased, multiomic spatial phenotyping with whole-slide imaging to identify biomarkers associated with response to ICI therapy in HNSCC. Citation Format: HaYeun Ji, Niyati Jhaveri, Ning Ma, Bassem B. Cheikh, Aditya Pratapa, James Monkman, Ken O’Byrne, Brett Hughes, Arutha Kulasinghe, Oliver Braubach. Single cell, multiomic spatial phenotyping of immunotherapy responses in head and neck cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5647.
Abstract 4083: <i>In vivo</i> efficacy of LGR5-targeting CAR-T cell therapies developed for the treatment of colorectal cancer
Authors: Dylan McPeake, Timona Tyllis, Caitlin Abbott, Jade Foeng, Veronika Bandara, Batjargal Gundsambuu, Elaheh Rohani-Rad, Silvana Napoli, Timothy Sadlon, Simon Barry, Shaun McColl
Journal: Cancer Research (2023)

Abstract While CAR-T cells have demonstrated significant efficacy in the treatment of haematological malignancies, there are many challenges to overcome in developing CAR-T cell therapies against solid tumours. In particular, the scarcity of recognised effective target antigens in solid tumours remains a significant hurdle. Leucine-rich repeat-containing G-protein coupled receptor (LGR5) is a cancer stem cell marker, which mediates important roles in tumor initiation and metastasis. Upregulated LGR5 expression in malignant cell contexts highlights this surface receptor as a promising target for CAR-T cell therapy. In this study, we evaluated the efficacy of LGR5-targeting CAR-T cells against a range of human cancers. We demonstrate that LGR5 is expressed, both in vitro and in vivo, by numerous human cancers, including colorectal, ovarian, hepatic, brain, and pancreatic cancer. LGR5-targeting CAR-T cells effectively kill LGR5-expressing cancer cells in in vitro cytotoxicity assays and display significant anti-tumor activity in vivo when administered at 1, 2 or 3 weeks post-tumor inoculation in a subcutaneous human colorectal cancer xenograft mouse model. Furthermore, LGR5-targeting CAR-T cells that induce primary tumor rejection confer complete protection against a secondary tumor challenge 5 weeks post-T cell transfer. In vivo spatiotemporal distribution and repeated dosing studies demonstrate that LGR5-targeting CAR-T cells accumulate at the tumor site until tumor elimination, do not persist in off-target organs by d28 post-tumor inoculation and are safe and well-tolerated under the conditions tested. Together, these results provide the foundation for furthering the development of LGR5-targeting CAR-T cells for use in the clinic against colorectal cancers and other solid tumours. Citation Format: Dylan McPeake, Timona Tyllis, Caitlin Abbott, Jade Foeng, Veronika Bandara, Batjargal Gundsambuu, Elaheh Rohani-Rad, Silvana Napoli, Timothy Sadlon, Simon Barry, Shaun McColl. In vivo efficacy of LGR5-targeting CAR-T cell therapies developed for the treatment of colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4083.
Abstract 2668: Long non-cording RNA TUG1 promotes cisplatin resistance in ovarian cancer via DNA polymerase eta
Authors: Ryosuke Sonobe
Journal: Cancer Research (2023)

Abstract Ovarian cancer (OVCA) is the most malignant gynecologic cancer. Despite the use of surgery and platinum-based chemotherapy, the 5-year survival rate is approximately 30% at the time of diagnosis. Cisplatin inhibits DNA synthesis by cross-linking DNA and then induces cell apoptosis. However, cisplatin resistance often causes treatment failure and tumor relapse in OVCA patients. To overcome the cisplatin resistance in OVCAs, we studied the mechanism of chemoresistance by a long non-coding RNA (lncRNA), TUG1 (taurine upregulated gene 1), which is associated with carcinogenesis and drug sensitivity in OVCAs. The expression level of TUG1 in cisplatin-resistant OVCA clinical samples is significantly higher than that of cisplatin-sensitive samples by public database. A depletion of TUG1 increased the sensitivity of OVCA cells to cisplatin together with upregulation of a set of miRNAs in vitro. We examined the targets of miRNAs and found that TUG1 depletion downregulates DNA polymerase eta (Polη) by upregulating the miRNAs. Polη is a major translesion DNA synthesis (TLS) DNA polymerase, which bypasses DNA lesions produced by DNA damaging agents and helps DNA replication. The expression level of Polη showed a positive correlation with that of TUG1 in OVCA clinical samples. Overexpression of Polη recovered cisplatin resistance in TUG1-depleted cells. Finally, cisplatin treatment combined with TUG1 depletion effectively inhibited tumor growth in xenograft mouse models, indicating the efficacy of TUG1 depletion in vivo. Our data provide a strong rationale for targeting TUG1 as a novel therapeutic approach to overcome cisplatin resistance in OVCA. Citation Format: Ryosuke Sonobe. Long non-cording RNA TUG1 promotes cisplatin resistance in ovarian cancer via DNA polymerase eta [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2668.
Abstract 1823: Overcoming siglec-9-mediated immunosuppression by using glycomimetics that block the binding of this receptor with its natural ligands
Authors: Lojain I. AlJohani, Manish Patankar, Weiping Tang, Christopher Stevens, Peng Teng
Journal: Cancer Research (2023)

Abstract MUC16, a 3-5 million Da mucin overexpressed by ovarian cancer cells binds to Siglec-9, an inhibitory receptor on immune cells. Upon binding to Siglec-9, MUC16 triggers inhibitory signaling in the immune cells that allows ovarian cancer cells to evade cytolytic immune responses. Ovarian and other tumors express a plethora of cell surface as well as secreted glycoproteins with glycans that are terminated with the Siglec-9 ligand, α-2,3-linked sialic acid. Therefore, targeting the sialic acid-Siglec-9 axis has been of major interest to augment antitumor immunity. Here, we demonstrate that synthetic glycomimetic Siglec-9 ligands have the potential to enhance the immune recognition of ovarian cancer cells. We first demonstrate, using siglec-9 chimeras, that the glycomimetics developed by our group inhibit the binding of Siglec-9 to its natural ligands. Our data showed that 50-fold excess of the glycomimetics over Siglec-9 chimera prevented the Siglec-9 chimera from binding to the OVCAR-3 cell line (P.value, 0.039). Additionally, we demonstrate that glycomimetics (#153 and 157) developed by our group, enhance the recognition of ovarian cancer cell targets by human NK cells. In healthy donor 1, CD107a expression was increased (21, 17, 19 %) when 0.01, 0.025, 0.05 mM concentration of glycomimetic 153 was used, respectively. A statistically significant increase (5%) in CD107a expression was observed when the NK cells were treated with 0.05 mM concentration of glycomimetic 157. At higher concentrations of glycomimetic 153 and 157, inhibition of CD107a was repeatedly observed. These experiments, therefore, suggest that there is likely a certain concentration range of the glycomimetic that can be used to overcome NK cell suppression occurring via Siglec-9. To our knowledge, these data are among the first to demonstrate that specially designed glycomimetics can be used to overcome the suppression of NK cells against ovarian cancer cells. Future studies will employ murine and humanized models to demonstrate the therapeutic potential of the Siglec-9-targeting glycopeptides in enhancing immune responses against epithelial ovarian cancer. Citation Format: Lojain I. AlJohani, Manish Patankar, Weiping Tang, Christopher Stevens, Peng Teng. Overcoming siglec-9-mediated immunosuppression by using glycomimetics that block the binding of this receptor with its natural ligands [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1823.
Abstract 3615: Targeting tumor-brain crosstalk in invasive brain metastases
Authors: Caitlyn Mourcos, Sarah M. Maritan, Matthew G. Annis, Georgia Kruck, Alexander Nowakowski, Anna-Maria Lazaratos, Kevin Petrecca, Peter Siegel
Journal: Cancer Research (2023)

Abstract Background: An estimated 20-40% of cancer patients develop brain metastases (BrM), mostly those affected by lung cancer, breast cancer or melanoma. Unfortunately, these patients suffer from poor outcomes and diminished quality of life. Few BrM treatment options beyond local therapy exist and this is often a short-term solution as 60% of resected BrM recur within 1 year. Our group discovered that patient prognosis is linked to BrM invasiveness, with highly invasive (HI) BrM more likely to recur, compared to minimally invasive (MI) BrM. This has presented us the opportunity to investigate exploitable biological mechanisms driving HI BrM. For instance, invasive signaling can be driven by microenvironmental proteins such as growth and immunological factors (cytokines) secreted by surrounding brain or cancer cells, through inter-cellular or self-feeding autocrine loops. Hypothesis: Considering the influence of secreted factors on cancer invasion and the brain microenvironment, I hypothesize that secretory profiling of BrM and brain parenchymal cells will be mechanistically insightful and help identify potential targetable drivers of BrM invasion. Results: To identify BrM invasion-related tumor- and brain-derived factors, I performed human- and mouse-specific high throughput Enzyme-Linked Immunosorbent Assay (ELISA)-based screens on conditioned media from mouse brain slices harboring intracranial MI or HI BrM patient-derived xenografts (PDX). This secretome screen reveals distinct MI and HI secretory profiles for melanoma, breast cancer and lung cancer BrMs and several HI BrM-derived factors of interest have been identified. Such factors are important to investigate as possible drivers of invasiveness in BrM through functional studies. Conclusion: BrM patients currently face a bleak prognosis, with few treatment options and a median survival of only 8-16 months. Considering the clinical availability of targeted therapies including inhibitors for growth factor-binding tyrosine kinases, antibody-drug conjugates, and immunotherapy, this project will help elucidate the cancer-brain crosstalk which may be exploited therapeutically with existing drugs in patients with frequently recurring HI BrM. ADDIN Citation Format: Caitlyn Mourcos, Sarah M. Maritan, Matthew G. Annis, Georgia Kruck, Alexander Nowakowski, Anna-Maria Lazaratos, Kevin Petrecca, Peter Siegel. Targeting tumor-brain crosstalk in invasive brain metastases. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3615.